PET Molecular Imaging in Drug Development: The Imaging and Chemistry Perspective

Abstract

Positron emission tomography with selective radioligands advances the drug discovery and development process by revealing information about target engagement, proof of mechanism, pharmacokinetic and pharmacodynamic profiles. Positron emission tomography (PET) is an essential and highly significant tool to study therapeutic drug development, dose regimen, and the drug plasma concentrations of new drug candidates. Selective radioligands bring up target-specific information in several disease states including cancer, cardiovascular, and neurological conditions by quantifying various rates of biological processes with PET, which are associated with its physiological changes in living subjects, thus it reveals disease progression and also advances the clinical investigation. This study explores the major roles, applications, and advances of PET molecular imaging in drug discovery and development process with a wide range of radiochemistry as well as clinical outcomes of positron-emitting carbon-11 and fluorine-18 radiotracers.

Keywords: PET molecular imaging; carbon-11; drug development; fluorine-18; radioligands.

Figure 1

The schematic representation of receptor imaging with positron emission tomography (PET) and the flow from radionuclide generation to PET Imaging output, where the initial step is the generation of positron-emitting radionuclides, the second step is the radiochemical synthesis, the third step is the preparation of suitable radiopharmaceutical formulation, the fourth step is the PET imaging data acquisition, the fifth step is the PET data pre and post-processing using software technologies, the last stage is the output of PET images reveal physiological changes based on radiotracer uptake corresponding to the intensity and dynamics in the color of images.

Figure 2

The roles of PET imaging studies in drug discovery and development, the PET advances the development of therapeutic drugs with various approaches like target engagement, proof of mechanism, proof of principle, and proof of concept at different stages of early and late-stage drug discovery research, and clinical development process.

Figure 3

The PET imaging applications in drug discovery and development, where the preclinical and clinical studies focused on pharmacokinetic profiles, pharmacodynamic actions, safety, efficacy, toxicity, dosage regimen, and response monitoring of a new drug candidate by studying behaviors of a radiotracer in living subjects.

Figure 4

Biopharmaceutical compartment analysis models. (A) One-tissue compartment, in which the whole tissue is considered as one compartment including the non-displaceable (free plus non-specific) along with the specifically bound. (B) Two-tissue compartment. In which two compartments are present in the tissue which include non-displaceable (free plus non-specific) and specific bound. The rate constants are generally obtained via dissociation constant from the tissue to the plasma.

Figure 5

Illustrates a clear differentiation between the abnormal conditions in the brain from a healthy human brain control using PET molecular imaging tools with selective radioligand, herein a few best examples were taken from (–39), such as [¹¹C]PBR28 showed high binding in different cortical regions of Alzheimer's Disease (AD) patient compared with a normal brain, the [¹¹C]PBR28 showed increased binding in frontal and temporal lobes in Frontotemporal Dementia (FD) compared with healthy controls, the [¹⁸F]FDOPA showed a little uptake in regions of caudate and putamen corresponding to nigrostriatal pathway in Parkinson's Disease (PD) patient from the healthy brain, and the [¹¹C]PK11195 showed uptake in the regions with high activation of microglia in a Multiple Sclerosis (MS) patient compared to a healthy normal brain.

Figure 6

The illustration of the treatment response of Rasagiline drug as a selective MAO-B inhibitor in patients with Parkinson's Disease (PD) using PET imaging studies, where the baseline and after treatment with a blocking agent PET studies were performed to calculate the percentage of receptor occupancy of the brain Monoamine Oxidase B (MAO-B) receptor by rasagiline using the selective radiotracer ¹¹C-L-Deprenyl, three different PD patients were taken for the studies and performed initial baseline PET study with ¹¹C-L-Deprenyl, followed by PET study with blocking agent rasagiline at different time intervals like immediate use, after 2–3 and 4–6 weeks to monitor the treatment response in PD condition, this case study was taken from (42).

Figure 7

Various synthetic approaches for 18F-radiofluorination of biomolecules. (A) Electrophilic radiofluorination of [¹⁸F]FDG. (B) Nucleophilic radiofluorination of [¹⁸F]FDG. (C) Transitional metal-mediated radiofluorination of [¹⁸F]F-DOPA. (D) Commonly used prosthetic groups for radiofluorination.

Figure 8

Various synthetic approaches for the generation of secondary precursors to developing carbon-11 inserted biomolecules.

Figure 9

The structures of target-specific novel ¹⁸F and ¹¹C-radiotracers for diagnosis of various conditions in oncology.

Figure 10

The structures of target-specific novel ¹⁸F and ¹¹C-radiotracers for diagnosis of various conditions in neurology.